Process for purifying 7-dimethylamino-6-demethyl-6-deoxytetracycline

ABSTRACT

A process for purifying 7-dimenthylamino-6-demethyl-6-deoxytetracycline represented by the following formula, ##STR1## which comprises dissolving 7-dimethylamino-6-demethyl-6-deoxytetracycline or its hydrochloride having a lower purity in a mixed solvent of an alcohol and water by using hydrochloric acid and then adjusting the pH of the solution to 3.5 to 4.5 to recrystallize the hydrochloride having a higher purity.

This application is a continuation of application Ser. No. 468,578,filed Jan. 23, 1990, now abandoned, which is a continuation-in-part ofapplication Ser. No. 222,886, filed July 22, 1988 now U.S. Pat. No.4,918,208.

FIELD OF THE INVENTION AND RELATED ART STATEMENT

This invention relates to a process for purifying a medicament. Moreparticularly, it relates to a process for purifying7-dimethylamino-6-demethyl-6-deoxytetracycline I, hereinafter referredto as "minocycline", an antibiotic substance of the tetracycline family:##STR2##

DESCRIPTION OF THE RELATED ART

Minocycline is an antibiotic substance useful as a medicament. Typicalknown methods for synthesizing minocycline include

(1) reductive dimethylamination of7-nitro-6-demethyl-6-deoxytetracycline with formaldehyde (U.S. Pat. No.3,226,436; J. Med. Chem., 10, 44 (1967); JP-B-42-8380,

(2) reductive dimethylamination of7-[1,2-bis(carbobenzyloxy)hydrazino]-6-demethyl-6-deoxytetracycline withformaldehyde (U.S. Pat. No. 3,403,179; JP-B-50-37666), and

(3) reductive dimethylamination of7-(4-sulfophenylazo)-6-demethyl-6-deoxytetracycline with formaldehyde(Fr. Add. No. 92,088). Minocycline obtained by any of the aforementionedmethods is isolated by pouring the reaction liquid after the reductivedimethyl-amination (wherein usually alcohols such as methyl cellosolve,methanol and ethanol are used as a solvent) into a large amount of asolvent which does not dissolve minocycline, such as ether or acetone,to precipitate crystals of minocycline (namely a "dilution method") orby extracting it with a water-immiscible organic solvent such aschloroform or ethyl acetate from the reaction liquid which has been madeneutral to prevent salt formation between minocycline and acids (namelyan "extraction method"). With regard to removal of formaldehyderemaining in the reaction liquid, no description is given in the priorreference. Since residual formaldehyde exerts an adverse effect offorming by-products, particularly in aqueous medium, by reacting withminocycline, it is preferably removed as completely as possible.

That is, the processes for producing minocycline comprise reductivedimethylation of 7-amino-6-demethyl-6-deoxytetracycline, which, forexample, is obtained by hydrogenation of7-nitro-6-demethyl-6-deoxytetracycline,7-[1,2-bis(carbobenzyloxy)hydrazino]-6-demethyl-6-deoxytetracycline or11a-chloro-6-demethyl-6-deoxy-7-(p-sulfophenylazo)tetracycline withhydrogen, using excess of formaldehyde but, after completion of thereaction, it is preferable to remove residual formaldehyde effectivelyfrom the reaction liquid to suppress the formation of by-products.

Although several methods are already known for removing formaldehydefrom a solution containing it and other compounds, it has been foundthat treatment with hydroxylamine or urea gives a particularly goodresult. Since it is already known that hydroxylamine reacts withcarbonyl compounds, it was expected that it would react also withminocycline which has carbonyl groups. Contrary to the expectation,however, no indication of a reaction between hydroxyl amine andminocycline was observed.

The removal of the residual formaldehyde in a reaction liquid is carriedout as follows:

The amount of hydroxylamine or urea to be used is usually 0.5 to 10moles, preferably 0.8 to 2 moles, per mole of formaldehyde used inexcess. Hydroxylamine may be used in any of the forms includinghydrochloride, sulfate, organic acid salts and free amine.

For treating a reaction liquid containing minocycline, formaldehyde andother impurities (wherein alcoholic solvents such as methyl cellosolve,methanol and ethanol are usually employed), with hydroxylamine or urea,there may be mentioned a method comprising adding hydroxylamine or ureadirectly to the reaction liquid, and one comprising dissolvinghydroxylamine or urea in water or other solvents beforehand and thenpouring to the solution, under stirring, the solution of minocyclinecontaining formaldehyde.

The treatment of a reaction liquid with hydroxylamine or urea may beusually carried out at 0° to 50° C. for 5 minutes to 10 hours.

There is no particular limitation as to the solvent used for dissolvinghydroxylamine or urea. Preferred examples of the solvent include water;alcohols such as methanol, butanol, methyl cellosolve and the like;aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide andthe like; esters such as ethyl acetate, butyl acetate and the like;ketones such as acetone, methyl ethyl ketone and the like; halogenatedhydrocarbons such as methylene chloride, chloroform and the like; andethers such as tetrahydrofuran, dioxane and the like.

The reaction liquid at the time of being treated with hydroxylamine orurea may be either acidic, neutral or basic. However, treatment underacidic to neutral conditions gives better results. If insoluble matterseparates out after the treatment, it may be removed by filtration.Particularly, when urea is used as a treating agent an insoluble polymertends to be formed, which is preferably filtered off.

The reaction liquid treated as described above, more preferably, is thensubjected to an adsorption treatment with an adsorbent.

In this process, a nonionic adsorption resin (high porous polymer) isused as the adsorbent. Typical examples thereof includestyrene-divinylbenzene type copolymers, substitutedstyrene-divinylbenzene type copolymers; methacrylic acid type polymers,styrene-allylacrylate type copolymers, other vinyl polymers orcopolymers, and the like polymers which have been formed into granules.As an index to the porosity of a nonionic adsorption resin, there isused the specific surface area. A nonionic adsorption resin having aspecific surface area of 30-2,000 m² /g are suitably used and thosehaving the area of 100-1,000 m² /g are particularly preferable. Theadsorption of minocycline to a nonionic adsorption resin is estimated tobe caused mainly by van der Waals force. As specific examples of suchabsorbents, there may be mentioned Diaion® HP-10, HP-20, HP-21, HP-30,HP-40, HP-50, SP-206, SP-207, SP-800, SP-900, HP-MG1MG and HP-MG2MG (allmfd. by Mitsubishi Chemical Industries Ltd.) and Amberlite® XAD-1,XAD-2, XAD-4, XAD-5 and XAD-7 (all mfd. by Rohm and Haas Co.), but theyare not limited thereto. With regard to a nonionic adsorption resin usedsuitably, detail descriptions are given, for example, in the followingreferences;

I & EC Product Research and Development, 7, 107 (1968);

"Amberlite XAD", published by Japan Organo Co., Ltd.);

U.S. Pat. No. 3,725,400.

The suitable amount of adsorbent to be used is 10-100 volumes relativeto unit weight of minocycline present in the solution to be treated(namely, 10-100 ml/1 g minocycline).

Before being subjected to such an adsorption treatment, the reactionliquid treated with hydroxylamine or urea is preferably diluted withwater to form an aqueous solution. If insoluble matter is formed bydilution with water it is removed by filtration. The solution is thenadjusted to a pH of 3-9, preferably 5-8, and subjected to adsorptionwith the aforesaid adsorbent. When the pH of the solution is not higherthan 3, adsorption of minocycline to the adsorbent is poor, whereas whenit is higher than 9 minocycline is liable to decompose, when thesolution to be treated has a pH of 5-8, 98% or more of minocyclinepresent in the solution are adsorbed suitably to the adsorbent. Theminocycline-containing aqueous solution to be subjected to theadsorption may contain water-soluble organic solvents such as methanol,ethanol, methyl cellosolve, DMF and the like and it is preferablyprepared such that water amounts to at least one third, more preferablyone half, of the total solution. The adsorption to the adsorbent can beaccomplished either by a continuous method (a column method) or by abatch method, the former method is preferable. The adsorption mayusually be carried out at room temperature (about 10-50° C.). Afterminocycline has been adsorbed to the absorbent, it is first developedwith a large amount of water to elute contaminants other than substancesof the tetracycline family. At this time, by-products formed during thereductive dimethylation, for example, amines formed by the decompositionof azo groups, reaction products between formaldehyde and hydroxylamine,reaction products between formaldehyde and urea, and the likesubstances, are eluted. Of course, the contaminates may also be removedbatchwise by washing with water. Thereafter, the purity of minocyclinecan be enhanced by washing with a dilute aqueous solution of an organicsolvent.

The eluent used for eluting minocycline adsorbed to the adsorbent is apolar organic solvent miscible with water. Particularly preferred is anorganic solvent to which an acid has been added in an equivalent molesor more to one mole of minocycline estimated to have been adsorbed. Theamount of eluent to be used is 1-10 times by volume, preferably 1.5-3times by volume, that of the adsorbent.

As examples of the polar organic solvent, there may be mentionedalkanols such as methanol, ethanol, isopropanol and the like;alkoxyalkanols such as 2-methoxyethanol, 2-ethoxyethanol,1-ethoxypropanol and the like; glycols such as ethylene glycol,propylene glycol and the like; and aprotic polar solvents such asdimethylformamide, dimethylacetamide, dimethylimidazolidinone, dimethylsulfoxide and the like. Particularly preferred are lower alkanols. Theacids added to the organic solvent are mineral acids such ashydrochloric acid, hydrobromic acid or sulfuric acid or organic acidssuch as oxalic acid, and are preferably hydrochloric acid or sulfuricacid. The amount of the acid is preferably about 1.5 to 3 moles per moleof minocycline estimated to have been adsorbed. The polar organicsolvent may contain water.

The eluate containing minocycline thus obtained is concentrated andadjusted to a pH of 4-8 to obtain crystals of minocycline (hydrate).Minocycline (hydrate) thus obtained has a high purity. If necessary,minocycline having more enhanced purity can be obtained by repeating theadsorption treatment alone according to the above-mentioned process.

After elution of minocycline, the adsorbent can be regenerated to theinitial state merely by washing it with a large amount of neutral water.In the process, the adsorbing capacity of the adsorbent was maintainedeven after an endurance test of repeated 50 times.

Even if treatment of a reaction liquid with hydroxylamine or urea and/oradsorption treatment of a low-purity minocycline with an adsorbent, someby-products are still often contained in minocycline thus treated. Acrude minocycline obtained by a dilution method or an extraction methodcontains many by-products and is not highly purified enough to be usedas a medicament.

Accordingly, development of an effective process for producingminocycline of low impurity content is eagerly awaited.

SUMMARY OF THE INVENTION

The present inventors has made extensive studies to establish a processfor obtaining minocycline of a high purity in a high yield which is freefrom by-products, and resultantly attained the present invention.

Thus, according to the present invention, there is provided a processfor purifying 7-dimethylamino-6-demethyl-6-deoxytetracycline(minocycline) which comprises dissolving7-dimethylamino-6-demethyl-6-deoxytetracycline or its hydrochloridehaving a lower purity in a mixed solvent of an alcohol and water byusing hydrochloric acid and then adjusting the pH of the solution toabout 3.5 to 4.5 to recrystallize the hydrochloride having a higherpurity.

DESCRIPTION OF PREFERRED EMBODIMENTS

The process of the present invention will now be described in detailbelow.

Minocycline used in the process of the present invention may be thosewhich are produced by any process. However, minocycline which isobtained after treatment of a reaction liquid with hydroxylamine or areaand adsorption treatment of a low-purity minocycline with an adsorbentis preferably used.

Purification is carried out in the following order. First, minocyclineto be purified or its hydrochloride is dispersed in a mixed solvent ofan alcohol and water and dissolved by adjusting the pH of the solvent tousually 0.1 to 2.5, more preferably 0.5 to 2.0 with hydrochloric acid.Subsequently, the resulting solution is treated, if necessary, withactivated carbon and adjusted to a pH of about 3.5 to 4.5 with a basiccompound, whereby high-purity minocycline hydrochloride precipitates.

An alcohol used in the process of the present invention is preferably alower alcohol such as methanol, ethanol, propanol, butanol, etc., but itis not limited thereto.

The mixing ratio of water to an alcohol is not critical, but it isdesirable that the water content is 10 to 50 wt.%.

The concentration of the substance to be purified in the solution alsois not critical, but it is 2 to 40 g/100 ml, preferably 5 to 25 g/100ml. The concentration lower than 2 g/100 ml lowers the percent recovery,and that higher than 40 g/100 ml lowers the purification efficiency,either of the both being not practical. The purification temperature is0° to 40° C., preferably 5° to 25° C. The temperature higher than 40° C.increases the following epimer (II) which is a by-product: ##STR3## ThepH at the time of dissolution of minocycline or its hydrochloride isusually 0.1 to 2.5, preferably 0.5 to 2.5, but the most preferred pH isusually 0.8 to 1.5. If necessary, a metallic ion-sequentering agent suchas EDTA may be added at the time of dissolution.

Subsequently, minocycline hydrochloride is precipitated by adjusting thepH of the hydrochloride solution to about 3.5 to 4.5 with a base.Examples of the base include ammonia, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, etc.

Purification process of the present invention is applied to a furtherpurification of minocycline obtained after treatment of a reactionliquid with hydroxylamine or urea and/or adsorption treatment of alow-purity minocycline with an adsorbent and to purification of alow-purity minocycline obtained by a dilution method or an extractionmethod which are mentioned above.

The present invention will further be described in detail below withreference to Reference Examples and Examples.

REFERENCE EXAMPLE 1

According to the method described in Fr. Add. No. 92,088, 30 g of11a-chloro-6-demethyl-6-deoxy-7-(4-sulfophenylazo)tetracycline and 30.8g of aqueous 37% formaldehyde aqueous solution were subjected tohydrogenation to obtain 7-amino-6-demethyl-6-deoxytetracycline andreductive methylation thereof in 600 ml of methyl cellosolve and in thepresence of a palladium-on-carbon catalyst. After the catalyst had beenfiltered off, 640 g of a yellowish orange methyl cellosolve solutioncontaining 16.3 g of minocycline (free form) was obtained. The solutioncontained minocycline (the intended product) and also4-dimethylaminobenzenesulfonic acid, formaldehyde and other impurities.

The solution was dissolved in 2000 ml of water containing 15.7 g ofhydroxylamine sulfate, then stirred at room temperature (20° C.) forabout 20 minutes, and adjusted to pH 7.4 with 20% sodium hydrxideaqueous solution. The solution was then passed through a columncontaining 400 ml of Diaion® HP-20 resin (a high porous polymer,styrene-divinylbenzene copolymer, specific surface area : 720 m² /g) toeffect adsorption (20° C.). Thereafter, development and elution werecarried out by using 10 l of deionized water to elute and removeby-products and impurities other than tetracyclines. Scarcely andeffluence of minocycline was observed during the operation.

Minocycline adsorbed to the adsorbent was developed and eluted with 1500ml of a methanol solution containing 7.5 g of concentrated hydrochloricacid to give 1300 ml of an eluate containing 16.0 g (98% recovery) ofminocycline. Liquid chromatographic analysis showed a purity of 95% ormore (areal percentage). The eluate was concentrated and adjusted to pH4.0 with 10% aqueous sodium hydroxide solution, whereby a pale yellowprecipitate separated out. It was then separated by filtration and driedunder vacuum at room temperature (20° C.) to give 15.3 g of minocyclinemonohydrochloride dihydrate as pale yellow powder. Analysis of theproduct by liquid chromatography showed a purity of 99.2% (potencyaccording to U.S. Pharmacopoeia : 910 μg/mg in terms of anhydride). Therecovery yield of minocycline after reductive dimethylation was 80.9%.The by-product formed in the aqueous solution by the action of residualformaldehyde amounted to 0.04%.

The mother liquor obtained after filtration of the precipitate formed byconcentrating the solution eluted from the adsorbent column followed bypH adjustment as described above contains a considerable amount ofminocycline. The mother liquor (containing 2.79 g of minocycline) wasadjusted to pH 7.4 with 20% sodium hydroxide aqueous solution andsubjected again to adsorption with Diaion® HP-20. Elution withmethanolhydrochloric acid conducted in the same manner as describedabove gave minocycline in a recovery of 90%.

REFERENCE EXAMPLE 2

In the same manner as in Reference Example 1 except the adsorbent usedwas altered from Diaion ® HP-20 to Diaion® SP-900, 15.5 g of minocyclinemonohydrochloride dihydrate was obtained. Analysis of the product byliquid chromatography showed a purity of 95.1% (potency : 876 μg/mg interms of anhydride).

REFERENCE EXAMPLE 3

According to the method described in JP-B-42-8380, 10 g of7-nitro-6-demethyl-6-deoxytetracycline sulfate was subjected tohydrogenation to obtain 7-amino-6-demethyl-6-deoxytetracycline andreductive dimethylation thereof, with 37% formaldehyde aqueous solutionadded thereto, in 200 ml of methyl cellosolve and in the presence of apalladium-on-carbon catalyst. After completion of the reaction, thecatalyst was filtered off. Resultantly, 280 g of a yellow solutioncontaining 7.0 g of minocycline (as the free form) was obtained.

The solution was then dissolved in 2000 ml of water containing 11.9 g ofhydroxylamine sulfate. The resulting solution was kept at roomtemperature (20° C.) for 30 minutes, then adjusted to pH 6.8 with 20%sodium hydroxide aqueous solution and subjected to adsorption withDiaion® HP-20 followed by elution in the same manner as in ReferenceExample 1. The eluate thus obtained was concentrated and then adjustedto pH 4.0 to give 5.3 g of minocycline monohydrochloride dihydrate.

Analysis of the product by liquid chromatography showed a purity of99.1% (potency : 909 μg/mg in terms of anhydride).

REFERENCE EXAMPLE 4

A reaction was carried out in the same manner as in Reference Example 1to give a reaction liquid containing minocycline (18.73 g as the freeform), formaldehyde, and other substances. In a 3-liter beaker wereplaced 2 l of water and 10.7 g of urea and, under stirring, the abovereaction liquid was gradually added thereto at room temperature (20°C.). After 6 hours treatment under the condition, light brown insolublematter separated out. The insoluble matter was filtered off and thefiltrate was gradually adjusted to neutral with 20% sodium hydroxideaqueous solution. The resulting treated reaction liquid was subjected toan adsorption treatment using Diaion® HP-20 as an adsorbent to makeminocycline adsorbed thereto. After water washing and nextly elutingwith 1500 ml of methanol containing 7.5 g of concentrated hydrochloricacid, methanol was distilled off from the eluate thus obtained. Theeluate was then adjusted to pH 4 to give white crystals. The crystal wasdried at room temperature (20° C.) under reduced pressure to give 17.2 gof minocycline monohydrochloride dihydrate. (The recovery yield was79.3%.) Analysis of the product by liquid chromatography showed a purityof 99.0%. The content of the by-product formed in aqueous medium by theaction of residual formaldehyde was 0.06%.

REFERENCE EXAMPLE 5

The procedure in Reference Example 1 were repeated except that 1 l ofAmberlite® XAD-7 (high porous polymer, methacrylic acid type polymer,specific surface area : 450 m² /g, average pore diameter : 90 Å) wasused as the adsorbent in place of Diaion® HP-20, to obtain 16.3 g ofminocycline monohydrochloride dihydrate.

Analysis of the product by liquid chromatography showed a purity of98.1% (potency : 880 μg/mg in terms of anhydride).

REFERENCE EXAMPLE 6

According to the method described in Fr. Add. No. 92,088, 30 g of11a-chloro-6-demethyl-6-deoxy-7-(p-sulfophenylazo)tetracycline washydrogenated to obtain 7-amino-6-demethyl-6-deoxytetracycline by using apalladium-on-carbon catalyst in 600 ml of methyl cellosolve, then 30.8 gof 37% formaldehyde aqueous solution was added to the reaction liquidand the mixture was subjected to reductive methylation in a hydrogenatmosphere.

After completion of the reaction, the insoluble catalyst was filteredoff to obtain a reaction liquid containing minocycline and formaldehyde.In a 3-liter beaker were placed 15.7 g of hydroxylamine semisulfate and2 l of water and then, under stirring, the above reaction liquid wasgradually added thereto at room temperature (20° C.). The final mixturehad a pH of 1.5. After 15 minutes of treatment under the conditions(under stirring), the mixture was gradually adjusted to neutral (pH :7.05) by the use of 20% sodium hydroxide aqueous solution.

The resulting reaction liquid thus treated was then treated with anadsorbent (Diaion® HP-20) to make minocycline adsorbed thereto. Afterwashing with water and nextly eluting with methanol containinghydrochloric acid, methanol was distilled off from the eluate obtained.The eluate was then adjusted to pH 4 to obtain minocycline as whitecrystal. The crystal was filtered off, and the product issued into thefiltrate was recovered from the filtrate by column adsorption. Theproduct was collected and dried under reduced pressure at roomtemperature (20° C.) to give 17.8 g of minocycline monohydrochloridedihydrate.

Analysis of the product by liquid chromatography revealed a purity of99.1%. The content of the by-product formed by the action of residualformaldehyde of minocycline was 0.04%.

EXAMPLE 1

Ten grams of a crude minocycline hydrochloride.dihydrate was suspendedat 20° to 25° C. in a mixed solvent of 50 ml of water and 50 ml ofmethanol and dissolved at a pH of 1.0 to 1.2 by adding conc.hydrochloric acid with stirring. Subsequently, 1 g of activated carbonand 10 mg of EDTA.2Na were added, and after 30 minutes' stirring, theactivated carbon was separated by filtration. To the filtrate was addeddropwise a 28% aqueous ammonia to adjust the pH of the filtrate to 4.0,whereby minocycline precipitated in the form of a hydrochloride. Thishydrochloride was separated by filtration and dried in vacuo to obtain9.5 g of a purified minocycline hydrochloride.dihydrate. Liquidchromatographic analysis of this product gave the following result(Table 1).

                  TABLE 1                                                         ______________________________________                                        Data of liquid chromatographic analysis                                       [area percentage (%)]                                                                                   Structurally                                                   Desired        unknown component                                              product                                                                              Epimer  (total)                                             ______________________________________                                        Material                                                                              (Crude)  95.6     3.0   1.4                                           Example 1                                                                             Purified 99.7     0.1   0.2                                                   product                                                               Example 2                                                                             Purified 99.8     0.1   0.1                                                   product                                                               Example 3                                                                             Purified 99.6     0.2   0.2                                                   product                                                               Compara-                                                                              Purified 99.0     0.2   0.8                                           tive    product                                                               example                                                                       ______________________________________                                    

EXAMPLE 2

Procedure was carried out in the same manner as in Example 1 except thata mixed solvent of 10 ml of water and 90 ml of methanol was usedinstead, to obtain 9.6 g of a purified minocyclinehydrochloride.dihydrate. Liquid chromatographic analysis of this productgave the result shown in Table 1.

EXAMPLE 3

Ten grams of the same crude minocycline hydrochloride.dihydrate as usedin Example 1 was suspended in a mixed solvent of 75 ml of water and 75ml of ethanol, and dissolved at a pH of 0.5 to 1.0 by adding conc.hydrochloric acid with stirring. Subsequently, 1 g of activated carbonwas added, and after stirring at 25° C. for 30 minutes, it wassuction-filtered. The filtrate was adjusted to a pH of 4.0 with a 10%aqueous caustic soda solution, whereby minocyclinehydrochloride.dihydrate precipitated. This product was separated byfiltration and dried in vacuo to obtain 9.4 g of a purified minocyclinehydrochloride.dihydrate. Liquid chromatographic analysis of this productgave the result shown in Table 1.

COMPARATIVE EXAMPLE

A comparative test was carried out as follows according to the methoddescribed in J. Org. Chem., 36, 723 (1971). Procedure was carried out inthe same manner as in Example 1 except that 100 ml of water was used asa purification solvent, to obtain 8.2 g of a purified minocyclinehydrochloride.dihydrate. Liquid chromatographic analysis of this productgave the result shown in Comparative example of Table 1. This resultshows that particularly removal of structurally unknown components wasinsufficient.

EXAMPLE 4

Ten grams of a crude minocycline [HPLC. purity, 94.8% (percentage area)]was suspended at 15° to 20° C. in a mixed solvent of 30 ml of water and45 ml of methanol and dissolved at a pH of 0.8 to 1.0 by adding conc.hydrochloric acid with stirring. Subsequently, 1 g of activated carbonand 10 mg of EDTA.2Na were added, and after 30 minutes' stirring, theactivated carbon was separated by filtration. To the filtrate was addeddropwise a 5% aqueous sodium hydroxide solution to adjust the pH of thefiltrate to 4.0, whereby minocycline precipitated in the form of ahydrochloride. This hydrochloride was separated by filtration and driedin vacuo to obtain 11.0 g of a purified minocycline hydrochloridedihydrate [HPLC. purity, 99.4% (area percentage)].

What is claimed is:
 1. A process for purifying7-dimethylamino-6-demethyl-6-deoxytetracycline represented by thefollowing formula (I) ##STR4## from impurities formed when said7-dimethylamino-6-demethyl-6-deoxytetracycline is obtained by reductivedimethylation of 7-amino-6-demethyl-6-deoxytetracycline withformaldehyde, comprising dissolving7-dimethyl-6-demethyl-6-deoxytetracycline or its hydrochloride having alower purity in a mixed solvent of an alcohol and water by usinghydrochloric acid and then adjusting the pH of the solution to 3.5 to4.5 to recrystallize the hydrochloride salt having a higher purity.
 2. Aprocess according to claim 1, wherein an alcohol is methanol.
 3. Aprocess according to claim 1, wherein7-dimethylamino-6-demethyl-6-deoxytetracycline or its hydrochloride saltis dissolved in a mixed solvent of methanol and water at a pH of 0.5 to2.5 and then the pH of the solution is adjusted to 3.5 to 4.5.